Benzamide derivatives as bradykinin antagonists

ABSTRACT

The present invention relates to new phenylsulfamoyl benzamide derivatives of formula (I) 
                         
wherein
         R 1 -R 5  and Z are as defined in the claims, and optical antipodes or racemates and/or salts and/or hydrates and/or solvates thereof, which are selective antagonists of bradykinin B1, to processes for producing these compounds, to pharmacological compositions containing them and to their use in therapy or prevention of painful and inflammatory conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. §371and claims benefit under 35 U.S.C. §119(a) of International ApplicationNo. PCT/HU2007/000102 having an International Filing Date of Oct. 27,2006, which claims the benefit of priority of HU P06 00808 having afiling date of Oct. 27, 2006.

FIELD OF THE INVENTION

The present invention relates to new phenylsulfamoyl benzamidederivatives of formula (I) and optical antipodes or racemates and/orsalts and/or hydrates and/or solvates thereof which are useful in thetreatment or prevention of painful and inflammatory processes. Thepresent invention also relates to the processes for producing compoundsof formula (I) and to pharmacological compositions containing the same.

BACKGROUND OF THE INVENTION

Kinins are endogenous peptides formed in plasma and peripheral tissuesin response to tissue injury or infection following catalytic cleavageof kininogens by kallikrein enzymes. Kinins play an important role inthe pathophysiological processes accompanying pain and inflammation.Their biological actions are mediated by two G-protein coupled membranereceptors, denoted B1 and B2. Both B1 and B2 receptors have been cloned[Biochem. Biophys. Res. Commun., 184 (1992) 260-268 and J. Biol. Chem.,269 (1994) 21583-21586] and the mechanisms regulating their expression,self-maintenance and signalling function is under intensiveinvestigations [Mol. Pharmacol., 56 (1999) 325-333 and J. Cell. Physiol.193 (2002) 275-286].

The first set of kinins, bradykinin (BK) and kallidin (LysBK)preferentially act through stimulation of constitutively expressed andrapidly desensitising B2 receptors, which are widely distributed in manytissues. On the other hand, their active carboxypeptidase metabolites,the second set of kinins, desArg⁹BK (DABK) and LysdesArg⁹BK (LysDABK)activate inducible and non-desensitising B1 receptors, which are rarelyexpressed under non-pathological conditions. Generally B1 receptorsrapidly appear after injuries of various natures (tissue trauma,infections, etc.). Thus the B1 receptor up-regulation appears to be partof a generalized response that includes the local co-expression(eventually up-regulation) of enzymes, receptors, autacoids, cytokinesand chemokines that notoriously play key roles in the early and lateresponses of tissues to various types of injury.

In animal models it has been demonstrated that there is a switch indominance of function from B2 to B1 in chronic inflammatory states.While the B2 receptor is implicated in the acute phase of theinflammatory and pain response, the B1 receptor is involved in thechronic phase of this response. The involvement of kinin receptors ininflammation and pain transduction has been supported by the results ofstudies on mice lacking bradykinin B1 receptors. B1 receptor deficientmice are different from wild-type mice in sensory functions, exhibitingincreased analgesic thresholds to noxious chemical and heat stimuli, anddrastic reduction in the accumulation of polymorphonuclear leukocytes atsites of inflammation [PNAS, 97 (2000) 8140-8145 and Neuropharmacology41 (2001) 1006-1012]. Furthermore the most original finding in B1receptor deficient mice was the direct evidence for a role of centralkinin receptors in nociception suggesting that the hypoalgesia seen inB1-receptor knockout mice is partly due to reduced central sensitisationin the spinal cord. However, apart from the above changes B1 knockoutmice were apparently normal without any apparent pathological changes.

Apart from the evidence of basal expression of B1 receptors on theperiphery recently more and more evidence shows that B1 receptors areconstitutively expressed ‘centrally’ in some neuronal elements,including the spinal cord and some higher structures as well. Thefunction of these receptors is unclear but they have been implicated inpain transmission and hyperalgesia. Therefore, B1 receptor antagonistsare believed to be useful in alleviating pain not only via peripheralsites but also to have possibly broader spectrum of analgesic effects ifthey block central B1 receptors as well [NeuroReport 11 (2000)4003-4005; NeuroReport, 12 (2001) 2311-2313; Neuroscience 107 (2001)665-673 and Neuroscience Letters 294 (2000) 175-178].

On the basis of scientific data bradykinin receptors are involved inmediation of pain and hyperalgesia in several ways. B1 receptorantagonists may have diverse modes of action. They have (1) indirect(‘peripheral’) effects on the nociceptors via inhibition of release ofother algogenic mediators. N.B. B1 receptors appear upon inflammatoryinduction on cells adjacent to sensory neurones (macrophages,fibroblasts or endothelial cells) are involved in releasing mediators(prostaglandins, cytokines and nitric oxide) that sensitize or activatethe nociceptors. (2) direct (‘peripheral’) effects on nociceptorsexpressing B1 receptors (constitutively) or upon induction and (3)‘central’ effects on pain processing in the superficial dorsal horn ofspinal cord.

Therefore, an orally active non-peptide bradykinin B1 receptorantagonist could be a potential therapeutic agent in the treatment ofchronic inflammatory pain.

Several patents and patent applications describe bradykinin B1 receptorantagonists which have different chemical structures. Such documents arefor instance the following international patent applications:WO200075107, WO02076964, WO04054584, WO02099388, WO05004810.

SUMMARY OF THE INVENTION

We have found a class of benzamide derivatives which have high affinityfor bradykinin B1 receptors and selectivity over bradykinin B2receptors. The selectivity is particularly important as the undesiredside effects of the compounds are much less pronounced.

The present invention relates to new phenylsulfamoyl benzamidederivatives of formula (I)

wherein

-   R¹ is hydrogen atom or C₁-C₄ alkyl group;-   R² is selected from (1) hydrogen atom; (2) C₁-C₆ straight or    branched alkyl group; (3) —(CH₂)_(n)—NH₂; (4) —(CH₂)_(n)—OH; (5)    —(CH₂)_(n)—CO—NH₂; (6) —(CH₂)_(n)—COOR^(c); (7) benzyl optionally    substituted with one or more hydroxy group or halogen atom; or-   R¹, R² and the carbon atom to which they are both attached together    form a 3-7 membered cycloalkyl ring;-   R³, R⁴ and R⁵ are independently of each other hydrogen atom; halogen    atom; cyano; nitro; amino; or amino substituted with one or more    C₁-C₄ alkyl group; trifluoromethyl; C₁-C₄ alkyl; C₁-C₄ alkoxy;    trifluoromethoxy; C₁-C₄ alkoxycarbonyl; —C(═O)—NH₂ or hydroxy group;-   Z is selected from (1) single bond; (2) oxygen atom; (3) CH₂    group; (4) CO group; (5) NR^(c) group; (6) S atom; (7) SO₂ group;-   Q is selected from

optionally substituted with —(CH₂)_(m)—OH group, or —(CH₂)_(n)—X—Pgroup;

optionally substituted with one or more C₁-C₄ alkyl group, one or morehalogen atom, —(CH₂)_(m)—OH group, —(CH₂)_(m)—NH₂ group,—(CH₂)_(m)—CO—NH₂ group, trifluoromethyl group, oxo group, —(CH₂)_(m)—CNgroup; —NH—CO—(C₁-C₄ alkyl) group, —NH—SO₂—(C₁-C₄ alkyl) group,—(CH₂)_(m)—COOR^(c) group, CO—NR^(c)R^(d) group, —(C₁-C₄ alkoxy) group,—NH—CO—(CH₂)_(m)—CF₃ group, —NH—SO₂—CH₂—CF₃ group;

group;

optionally substituted with oxo group, —SO₂—(C₁-C₄ alkyl) group, C₁-C₄alkyl group, —CO—(C₁-C₄ alkyl) group, —(CH₂)_(m)—O—(CH₂)_(m)—OH group,—(CH₂)_(m)—OH group, —SO₂—NR^(c)R^(d) group, —CO—NR^(c)R^(d) group;

group;

group;

group;

optionally substituted with —(CH₂)_(m)—OH group;

group;

group;

group;

-   Y is selected from (1) —(CH₂)_(n)—NR^(a)R^(b); (2) —(CH₂)_(n)—X—P    group;-   n is an integer from 0 to 6;-   m is an integer from 0 to 3;-   X is selected from (1) single bond; (2) oxygen atom; (3) —CO—NR^(c)    group; (4) CO or SO₂ group;-   P is selected from (1) phenyl group, optionally substituted with one    or more halogen atom, hydroxy, cyano, amino or C₁-C₄ alkyl    group; (2) a saturated, partially unsaturated or aromatic 4-7    membered ring containing 1-3 heteroatom selected from O, S, SO₂ and    N; wherein said ring is optionally substituted with one or more    halogen atom, oxo, hydroxy, cyano, amino or C₁-C₄ alkyl group; (3)    C₅-C₈ cycloalkyl group;-   R^(a) and R^(b) are (1) hydrogen atom, with the proviso that R^(a)    and R^(b) can not be simultaneously hydrogen atom; (2) straight or    branched C₁-C₆ alkyl group; (3) R^(a), R^(b) and the nitrogen atom    to which they are both attached together form a saturated, partially    unsaturated or aromatic 4-7 membered ring containing 0-3 heteroatom    (in addition to the nitrogen atom to which R^(a) and R^(b) attached)    selected from O, S, SO₂ and N; wherein said ring is optionally    substituted with one or more halogen atom, oxo, cyano, hydroxy or    C₁-C₄ alkyl group;-   R^(c) is hydrogen atom or C₁-C₄ alkyl group;-   R^(d) is hydrogen atom, C₁-C₄ alkyl group, C₁-C₄ hydroxyalkyl group,    C₃-C₈ cycloalkyl group;-   R^(e) is hydrogen atom, C₁-C₄ alkyl group, benzyl group;-   A is (1) a C₄-C₇ cycloalkyl ring; (2) a saturated, partially    unsaturated or aromatic 5-7 membered ring containing 0-4 heteroatom    including W¹ selected from O, S, SO₂ and N; wherein said ring is    optionally substituted with one or more halogen atom, oxo, cyano,    hydroxy, amino, phenyl or C₁-C₄ alkyl group;-   B is a saturated, partially unsaturated or aromatic 4-7 membered    ring containing 1-3 heteroatom selected from O, S, SO₂ and N;    wherein said ring is optionally substituted with one or more halogen    atom, oxo, cyano, hydroxy, amino, phenyl or C₁-C₄ alkyl group;-   W¹ is carbon atom, nitrogen atom, or CH group;-   W² is oxygen atom, sulfur atom, NH, CH₂ or SO₂ group;    and optical antipodes or racemates and/or salts and/or hydrates    and/or solvates thereof.

The invention also relates to the pharmaceutical compositions containingthe compounds of formula (I) or optical antipodes or racemates or saltsor hydrates or solvates thereof as active ingredient.

Furthermore objects of the present invention are the synthesis ofcompounds of formula (I), and the chemical and pharmaceuticalmanufacture of medicaments containing these compounds, as well as themethods of treatment with these compounds, which means administering toa mammal to be treated—including human—effective amount/amounts ofcompounds of formula (I) of the present invention as such or asmedicament.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new bradykinin B1 receptor antagonistphenylsulfamoyl benzamide derivatives of formula (I)

wherein

-   R¹ is hydrogen atom or C₁-C₄ alkyl group;-   R² is selected from (1) hydrogen atom; (2) C₁-C₆ straight or    branched alkyl group; (3) —(CH₂)_(n)—NH₂; (4) —(CH₂)_(n)—OH; (5)    —(CH₂)_(n)—CO—NH₂; (6) —(CH₂)_(n)—COOR^(c); (7) benzyl optionally    substituted with one or more hydroxy group or halogen atom; or-   R¹, R² and the carbon atom to which they are both attached together    form a 3-7 membered cycloalkyl ring;-   R³, R⁴ and R⁵ are independently of each other hydrogen atom; halogen    atom; cyano; nitro; amino; or amino substituted with one or more    C₁-C₄ alkyl group; trifluoromethyl; C₁-C₄ alkyl; C₁-C₄ alkoxy;    trifluoromethoxy; C₁-C₄ alkoxycarbonyl; —C(═O)—NH₂ or hydroxy group;-   Z is selected from (1) single bond; (2) oxygen atom; (3) CH₂    group; (4) CO group; (5) NR^(c) group; (6) S atom; (7) SO₂ group;    -   Q is selected from

optionally substituted with —(CH₂)_(m)—OH group, or —(CH₂)_(n)—X—Pgroup;

optionally substituted with one or more C₁-C₄ alkyl group, one or morehalogen atom, —(CH₂)_(m)—OH group, —(CH₂)_(m)—NH₂ group,—(CH₂)_(m)—CO—NH₂ group, trifluoromethyl group, oxo group, —(CH₂)_(m)—CNgroup; —NH—CO—(C₁-C₄ alkyl) group, —NH—SO₂—(C₁-C₄ alkyl) group,—(CH₂)_(m)—COOR^(c) group, —CO—NR^(c)R^(d) group, —(C₁-C₄ alkoxy) group,—NH—CO—(CH₂)_(m)—CF₃ group, —NH—SO₂—CH₂—CF₃ group;

group;

optionally substituted with oxo group, —SO₂—(C₁-C₄ alkyl) group, C₁-C₄alkyl group, —CO—(C₁-C₄ alkyl) group, —(CH₂)_(m)—O—(CH₂)_(m)—OH group,—(CH₂)_(m)—OH group, —SO₂—NR^(c)R^(d) group, —CO—NR^(c)R^(d) group;

group;

group;

group;

optionally substituted with —(CH₂)_(m)—OH group,

group;

group;

group;

-   Y is selected from (1) —(CH₂)_(n)—NR^(a)R^(b); (2) —(CH₂)_(n)—X—P    group;-   n is an integer from 0 to 6;-   m is an integer from 0 to 3;-   X is selected from (1) single bond; (2) oxygen atom; (3) —CO—NR^(c)    group; (4) CO or SO₂ group;-   P is selected from (1) phenyl group, optionally substituted with one    or more halogen atom, hydroxy, cyano, amino or C₁-C₄ alkyl    group; (2) a saturated, partially unsaturated or aromatic 4-7    membered ring containing 1-3 heteroatom selected from O, S, SO₂ and    N; wherein said ring is optionally substituted with one or more    halogen atom, oxo, hydroxy, cyano, amino or C₁-C₄ alkyl group; (3)    C₅-C₈ cycloalkyl group;-   R^(a) and R^(b) are (1) hydrogen atom, with the proviso that R^(a)    and R^(b) can not be simultaneously hydrogen atom; (2) straight or    branched C₁-C₆ alkyl group; (3) R^(a), R^(b) and the nitrogen atom    to which they are both attached together form a saturated, partially    unsaturated or aromatic 4-7 membered ring containing 0-3 heteroatom    (in addition to the nitrogen atom to which R^(a) and R^(b) attached)    selected from O, S, SO₂ and N; wherein said ring is optionally    substituted with one or more halogen atom, oxo, cyano, hydroxy or    C₁-C₄ alkyl group;-   R^(c) is hydrogen atom or C₁-C₄ alkyl group;-   R^(d) is hydrogen atom, C₁-C₄ alkyl group, C₁-C₄ hydroxyalkyl group,    C₃-C₈ cycloalkyl group;-   R^(e) is hydrogen atom, C₁-C₄ alkyl group, benzyl group;-   A is (1) a C₄-C₇ cycloalkyl ring; (2) a saturated, partially    unsaturated or aromatic 5-7 membered ring containing 0-3 heteroatom    selected from O, S, SO₂ and N; wherein said ring is optionally    substituted with one or more halogen atom, oxo, cyano, hydroxy,    amino, phenyl or C₁-C₄ alkyl group;-   B is a saturated, partially unsaturated or aromatic 4-7 membered    ring containing 1-3 heteroatom selected from O, S, SO₂ and N;    wherein said ring is optionally substituted with one or more halogen    atom, oxo, cyano, hydroxy, amino, phenyl or C₁-C₄ alkyl group;-   W¹ is carbon atom, nitrogen atom, or CH group;-   W² is oxygen atom, sulfur atom, NH, CH₂ or SO₂ group;    and optical antipodes or racemates and/or salts and/or hydrates    and/or solvates thereof.

The invention also relates to the pharmaceutical compositions containingthe compounds of formula (I) or optical antipodes or racemates or saltsor hydrates or solvates thereof as active ingredient.

Furthermore objects of the present invention are the synthesis ofcompounds of formula (I), and the chemical and pharmaceuticalmanufacture of medicaments containing these compounds, as well as themethods of treatment with these compounds, which means administering toa mammal to be treated—including human—effective amount/amounts ofcompounds of formula (I) of the present invention as such or asmedicament.

The term “halogen” substituent denotes fluorine, chlorine, bromine oriodine atoms. The term C₁-C₄ alkyl group used in the present descriptiondenotes methyl, ethyl, normal- and isopropyl and different butyl groups.These C₁-C₄ alkyl groups can be in the C₁-C₄ alkoxy groups and C₁-C₄hydroxyalkyl groups.

The 4-7 membered heterocyclic ring in the meaning of R^(a) and R^(b) canbe e.g. piperidine, pyrrolidine, piperazine, homopiperazine, morpholine,thiomorpholine and the like.

The 4-7 membered heterocyclic ring in the meaning of P and B can be e.g.imidazole, triazole, oxazol, thiazole, tetrazole, furan,tetrahydrofuran, pyrimidine, pyridine, piperidine, pyrrolidine,pyrazine, piperazine, homopiperazine, morpholine, thiomorpholine and thelike.

The saturated, partially unsaturated or aromatic 5-7 membered ring inthe meaning of A can be e.g. imidazole, triazole, oxazol, thiazole,tetrazole, pyrimidine, pyridine, piperidine, pyrrolidine, pyrazine,piperazine, homopiperazine, morpholine, thiomorpholine and the like.

The invention relates also to the salts of compounds of formula (I)formed with acids or bases.

Both organic and inorganic acids can be used for the formation of acidaddition salts. Suitable inorganic acids can be e.g. hydrochloric acid,sulfuric acid and phosphoric acid. Representatives of monovalent organicacids can be e.g. formic acid, acetic acid, trifluoroacetic acid,propionic acid, and different butyric acids, valeric acids and capricacids. Representatives of bivalent organic acids can be e.g. oxalicacid, malonic acid, maleic acid, fumaric acid and succinic acid. Otherorganic acids can also be used, such as hydroxy acids e.g. citric acid,tartaric acid, or aromatic carboxylic acids e.g. benzoic acid orsalicylic acid, as well as aliphatic and aromatic sulfonic acids e.g.methanesulfonic acid and p-toluenesulfonic acid. Especially valuablegroup of the acid addition salts is in which the acid component itselfdoes not have therapeutical effect in the applied dose or it does nothave unfavorable influence on the effect of the active ingredient. Theseacid addition salts are pharmaceutically acceptable acid addition salts.The reason why acid addition salts, which do not belong to thepharmaceutically acceptable acid addition salts belong to the presentinvention is, that in given case they can be advantageous in thepurification and isolation of the desired compounds.

Among the salts formed with bases especially important are the saltsformed with alkali metals, e.g. sodium, potassium, alkaline-earthmetals, e.g. calcium and magnesium, as well as with ammonia or organicamines. The latter bases can have further substituents, e.g. hydroxy oramino groups, which can influence e.g. the solubility and the handlingof the product. The salts formed with bases are pharmaceuticallyacceptable base addition salts.

According to the invention the compounds of formula (I) can besynthesized by reacting an amine derivative of formula (II)

wherein the meaning of R³, R⁴ and R⁵ is as described above for theformula (I)—with sulfonyl chloride of formula (III)

then the so obtained phenylsulfamoyl benzoic acid derivative of formula(IV)

wherein the meaning of R³, R⁴ and R⁵ is as described above for theformula (I)—is reacted with an amino acid of formula (V)

wherein the meaning of R¹ and R² is as described above for the formula(I) and R is C₁-C₄ alkyl- and the so obtained compound of formula (VI)

wherein the meaning of R¹, R², R³, R⁴, R⁵ and R is as defined above—ishydrolyzed to furnish a carboxylic acid derivative of formula (VII)

wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as defined above—finallythe latter is reacted with an amine derivative Q and the obtainedphenylsulfamoyl benzamide derivative of formula (I) in given case can betransformed into an other compound of formula (I) by introducing newsubstituents and/or modifying or removing the existing ones, and/or saltformation and/or liberating the compound from salts.

The sulfonylation reaction is preferably carried out in a propersolvent, preferably in the presence of a base. The reactions arefollowed by thin layer chromatography. The necessary reaction time is6-20 h. The work-up of the reaction mixture can be carried out bydifferent methods.

a) The reaction mixture is concentrated and the product is isolated bycrystallization or extraction. If the crude product is not pure enough,then column chromatography can be used for the purification of it. Thecolumn chromatography is carried out either on normal phase usingKieselgel 60 as adsorbent and different solvent systems, e.g.n-hexane/ethyl acetate, chloroform/methanol, dichloromethane/ethylacetate or chloroform/acetone as eluents, or on reversed phase usingYMC-Pack ODS-AQ type packings (produced by YMC) andacetonitrile/water/trifluoroacetic acid or acetonitrile/water/aceticacid as eluent.

b) The reaction mixture is poured into ice-water and the product isisolated by filtration or extraction. The crude product is crystallizedor purified by column chromatography as described above. The structuresof the products are determined by IR, NMR and mass spectrometry.

Hydrolysis of a compound of formula (VI) can be carried out with a base,e.g. alkali metal hydroxide, preferably sodium or lithium hydroxide, orwith an acid, e.g. organic acid, preferably trifluoroacetic acid.

The amide bond formations are preferably carried out by preparing anactive derivative from a carboxylic acid of formula (IV) or (VII) whichis reacted with an amino acid of formula (V) or an amine Q,respectively, preferably in the presence of a base.

The transformation of a carboxylic acid into an active derivative can becarried out in situ during the amide bond formation in a proper solvent(e.g. to dimethylformamide, acetonitrile, chlorinated hydrocarbons orhydrocarbons or the mixture thereof). The active derivatives can be acidchlorides (e.g. prepared from carboxylic acid with thionyl chloride),mixed anhydrides (e.g. prepared from carboxylic acid with isobutylchloroformate in the presence of a base, e.g. triethylamine), activeesters (e.g. prepared from carboxylic acid with hydroxybenztriazol(HOBt) and dicyclohexyl-carbodiimide (DCC) orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) in the presence of a base e.g. triethylamine). The activederivatives can be prepared at a temperature in the range of 0° C. toroom temperature. A proper amino acid of formula (V) or an amine Q isadded as a base or as a salt formed with inorganic acid to the soobtained solution or suspension in the presence of a base, e.g.triethylamine, needed for the liberation of the amine. The condensationreactions are followed by thin layer chromatography. The necessaryreaction time is 6-20 h. The work-up of the reaction mixture can becarried out by different methods.

a) The reaction mixture is concentrated, and the residue is crystallizedor extracted with a proper organic solvent and in given case purified bycolumn chromatography. The column chromatography is carried out onnormal phase using Kieselgel 60 as adsorbent and different solventsystems, e.g. toluene/methanol, chloroform/methanol or toluene/acetone,as eluents or on reversed phase using YMC-Pack ODS-AQ type packings(produced by YMC) and acetonitrile/water/trifluoroacetic acid oracetonitrile/water/acetic acid as eluent.

b) The reaction mixture is directly purified by column chromatography asdescribed above to yield the pure product.

The structures of the products are determined by IR, NMR and massspectrometry.

The obtained benzamide derivatives of formula (I)—independently from themethod of preparation—in given case can be transformed into anothercompound of formula (I) by introducing further substituents and/ormodifying and/or removing the existing ones, and/or formation of saltswith acids and/or liberating the benzamide derivative of formula (I)from the obtained acid addition salts by treatment with a base and/orthe free sulfonamide derivative of formula (I) can be transformed into asalt by treatment with a base.

For instance cleaving the benzyl group from N-benzyl group, which standsfor R^(e), can be carried out e.g. with catalytic hydrogenation or withchloroethyl chloroformate in a proper solvent. The compounds of formula(I) containing free hydroxy group can be transformed into acyloxy orsulfoxy derivatives with different acylating or sulfonylating agents.The reactions can be carried out for example in chlorinated hydrocarbonsusing acid chloride or acid anhydride as acylating agent in the presenceof a base (e.g. triethylamine or sodium carbonate). The sulfonamidederivatives of formula (I) containing a nitro group can be transformedinto amines by reduction and the amines can be further reacted to giveacid amides as described for the acylation of hydroxy groups orcarbamate derivatives can be synthesized. Ester groups can be hydrolyzedand the obtained free carboxylic acids can be transformed into amides byreacting with proper amine derivatives. N-(tert-Butoxycarbonyl) groupcan be cleaved by organic or inorganic acids (e.g. trifluoroacetic acidor hydrogen chloride). Cyano groups can be transformed into amide,N-hydroxy-amidine or different N-containing heterocyclic groups.

Most of the amino acids of formula (V) and amines Q are eithercommercially available or can be synthesized by different known methods.The syntheses of some new amines Q are described in the Examples.Following these procedures the other amines Q can also be prepared.

The compounds of the present invention as well as their pharmaceuticallyacceptable salts or hydrates or solvates can be used as such or suitablyin the form of pharmaceutical compositions. These compositions (drugs)can be in solid, liquid or semiliquid form and pharmaceutical adjuvantand auxiliary materials can be added, which are commonly used inpractice, such as carriers, excipients, diluents, stabilizers, wettingor emulsifying agents, pH- and osmotic pressure-influencing, flavoringor aromatizing, as well as formulation-promoting orformulation-providing additives.

The dosage required to exert the therapeutical effect can vary withinwide limits and will be fitted to the individual requirements in each ofthe particular case, depending on the stage of the disease, thecondition and the bodyweight of the patient to be treated, as well asthe sensitivity of the patient against the active ingredient, route ofadministration and number of daily treatments. The actual dose of theactive ingredient to be used can safely be determined by the attendingphysician skilled in the art in the knowledge of the patient to betreated.

The pharmaceutical compositions containing the active ingredientaccording to the present invention usually contain 0.01 to 100 mg ofactive ingredient in a single dosage unit. It is, of course possiblethat the amount of the active ingredient in some compositions exceedsthe upper or lower limits defined above.

The solid forms of the pharmaceutical compositions can be e.g. tablets,dragées, capsules, pills or lyophilized powder ampoules useful for thepreparation of injections. Liquid compositions are the injectable andinfusable compositions, fluid medicines, packing fluids and drops.Semiliquid compositions can be ointments, balsams, creams, shakingmixtures and suppositories.

For the sake of a simple administration it is suitable if thepharmaceutical compositions comprise dosage units containing the amountof the active ingredient to be administered once, or a few multiples ora half, third or fourth part thereof. Such dosage units are e.g.tablets, which can be powdered with grooves promoting the halving orquartering of the tablet in order to exactly administer the requiredamount of the active ingredient.

Tablets can be coated with an acid-soluble layer in order to assure therelease of the active ingredient content after leaving the stomach. Suchtablets are enteric-coated. A similar effect can be achieved also byencapsulating the active ingredient.

The pharmaceutical compositions for oral administration can contain e.g.lactose or starch as excipients, sodium carboxymethylcellulose,methylcellulose, polyvinyl pyrrolidine or starch paste as binders orgranulating agents. Potato starch or microcrystalline cellulose is addedas disintegration agents, but ultraamylopectin or formaldehyde caseincan also be used. Talcum, colloidic silicic acid, stearin, calcium ormagnesium stearate can be used as antiadhesive and lubricants.

The tablets can be manufactured e.g. by wet granulation, followed bypressing. The mixed active ingredients and excipients, as well as ingiven case part of the disintegrants are granulated with an aqueous,alcoholic or aqueous alcoholic solution of the binders in an appropriateequipment, then the granulate is dried. The other disintegrants,lubricants and antiadhesive agents are added to the dried granulate, andthe mixture is pressed to a tablet. In given case the tablets are madewith halving groove to ease the administration.

The tablets can be made directly from the mixture of the activeingredient and the proper auxiliaries by pressing. In given case, thetablets can be coated by using additives commonly used in thepharmaceutical practice, e.g. stabilizers, flavoring, coloring agents,such as sugar, cellulose derivatives (methyl- or ethylcellulose, sodiumcarboxymethylcellulose, etc), polyvinyl pyrrolidone, calcium phosphate,calcium carbonate, food coloring agents, food laces, aroma agents, ironoxide pigments, etc. In the case of capsules the mixture of the activeingredient and the auxiliaries is filled into capsules.

Liquid oral compositions, e.g. suspensions, syrups, elixirs can be madeby using water, glycols, oils, alcohols, coloring and flavoring agents.

For rectal administration the composition is formulated in suppositoriesor clysters. The suppository can contain beside the active ingredient acarrier, so called adeps pro suppository. Carriers can be vegetableoils, such as hydrogenated vegetable oils, triglycerides of C₁₂-C₁₈fatty acids (preferably the carriers under the trade name Witepsol). Theactive ingredient is homogeneously mixed with the melted adeps prosuppository and the suppositories are moulded.

For parenteral administration the composition is formulated as injectionsolution. For manufacturing the injection solution the activeingredients are dissolved in distilled water and/or in different organicsolvents, such as glycolethers, in given case in the presence ofsolubilizers, e.g. polioxyethylensorbitane-monolaurate, -monooleate, ormonostearate (Tween 20, Tween 60, Tween 80). The injection solution canalso contain different auxiliaries, such as conserving agents, e.g.ethylendiamine tetraacetate, as well as pH adjusting agents and buffersand in given case local anaesthetic, e.g. lidocain. The injectionsolution containing the active ingredient of the invention is filteredbefore it is filled into ampoules, and it is sterilized after filling.

If the active ingredient is hygroscopic, then it can be stabilized byliophylization.

Utilities

The compounds of the present invention are bradykinin receptorantagonists, in particular selective bradykinin B1 receptor antagonists,consequently are useful in the treatment or prevention of painful andinflammatory processes. The compounds would be effective in thetreatment of pain including, e.g., chronic pain, particularlyinflammatory pain, hyperalgesia, bone and joint pain (osteoarthritis),repetitive motion pain, myofascial pain (muscular injury, fibromyalgia),visceral pain (ulcerative colitis, pancreatitis, cystitis, uveitis),perioperative pain (general surgery, gynecological), postoperative pain(postsurgical pain syndrome), posttraumatic pain (e.g. sprains orfracture), neuropathic pain (postherpetic neuralgia, nerve injury,phantom limb pain, mononeuropthy, polyneuropathy) dental pain, andcancer pain. Furthermore for the treatment of pain associated withangina, menstruation, diabetic vasculopathy, post capillary resistanceor diabetic symptoms associated with insulitis (e.g. hyperglycemia,diuresis, proteinurea and increased nitrite and kallikrein urinaryexcretion), diabethic hyperalgeisa. Moreover the compounds may be usedfor the treatment angioedema, atherosclerosis, septic shock e.g. asanti-hypovolemic and/or anti-hypotensive agents, and sepsis. They may beused as smooth muscle relaxants for the treatment of spasm of thegastrointestinal tract or uterus. Further, the compounds of thisinvention can additionally be used to treat inflammatory skin disorders,such as psoriasis and eczema, and skin injuries including burning andsunburning (UV-erythema and pain). The compounds may be used to treatinflammatory pain of varied origins (e.g. rheumatoid arthritis,rheumatic disease, tenosynovitis, liver disease, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease, nephritis,allergic rhinitis, vasomotor rhinitis, uveitis, gingivitis), allergies.Such compounds may be used therapeutically to treat inflammatory airwaysdisease e.g. chronic obstructive pulmonary disease, adult respiratorydistress syndrome, bronchitis, pneumonia, asthma. They may be used tocontrol, restrict or reverse airways hyperreactivity in asthma, to treatintrinsic and extrinsic asthma including allergic asthma (atopic ornon-atopic), occupational asthma, viral or bacterial exacerbated asthma,other non-allergic asthmas, “wheezy-infant syndrome”, as well asexercise-induced bronchoconstriction. They may be effective againstpneumoconiosis, including aluminosis, antracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.Additionally, they may be effective in some neurological disorders, e.g.against multiple sclerosis, Alzheimer's disease, epilepsy, cerebraledema, headache including cluster headache, migraine includingprophylactic and acute use, as well as closed head trauma.

Biological Evaluation

Functional Assay:

Assessment of Antagonist Potency at B1 and B2 Receptors In Vitro byMeasurement of Cytosolic Calcium Ion Concentration with a Plate ReaderFluorimeter in Cells Expressing Recombinant Human B1 or B2 Receptors

Cell Culture

Chinese hamster ovary (CHO) cells stably expressing recombinant human B1(CHO-B1, Euroscreen) or B2 (CHO-B2, Perkin-Elmer) receptors werecultured in Dulbecco's Modified Eagle's Medium (DMEM) containing 10%Fetal Calf Serum (FCS), 100 U/ml penicillin, 0.1 mg/ml streptomycin,0.25 μg/ml amphotericin B, 1% Minimum Essential Medium Eagle (MEM), nonessential amino acid solution, 600 μg/ml G418, 1% pyruvate (for the B2cell line). Cells were kept at 37° C. in a humidified incubator in anatmosphere of 5% CO₂/95% air and were passaged 1:4 three times a week.Cells were plated at 1.5-2.5×10⁴ cell/well on standard 96-wellmicroplates, measurements of cytosolic calcium ion concentration([Ca²⁺]_(i)) were carried out 1-2 days after cell plating.

Fluorimetric Measurement of Cytosolic Calcium Concentration

Measurements of [Ca²⁺]_(i) were carried out on CHO-B1 and CHO-B2 cellsstably expressing human B1 and B2 receptors, respectively. Cells weregrown in standard 96-well microplates and before the measurement wereloaded with a fluorescent Ca²⁺-sensitive dye, fluo-4/AM (2 μM): afterremoving the culture medium the dye was added to the cells (dissolved inassay buffer: 145 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 2 mM CaCl₂, 10 mMHEPES, 20 mM D-glucose, 2 mM probenecid, 100 μl/well) and cells wereincubated at 37° C. in a humidified incubator in an atmosphere of 5%CO₂/95% air for 40-120 min. To stop dye loading cells were washed twicewith assay buffer. After washing, various concentrations of the testcompounds (diluted in extracellular medium from a DMSO stock solution,final DMSO concentration was <0.1%) or buffer were added to each welldepending on the experimental setup. After incubation at 37° C. for20-25 min. baseline and agonist-evoked changes of [Ca²⁺]_(i) weremeasured column by column with a plate reader fluorimeter (FluoroskanAscent, Labsystems). Excitation and detection of emission was carriedout from the bottom of the plate. Filters used for Fluo-4: excitationfilter—485 nm, emission filter—538 nm. The whole measurement process wasperformed at 37° C. and was controlled by custom software. Inhibitorypotency of the test compounds was assessed by measuring the reduction inthe agonist-evoked [Ca²⁺]_(i)-elevation in the presence of differentconcentrations of the compounds. The agonists were LysDABK for CHO-B1,and bradykinin for CHO-B2 cells. Agonists were applied at an EC₈₀concentration, the EC₈₀-values were derived from daily determineddose-response curves. Fluorescence data were expressed as ΔF/F(fluorescence change normalized to baseline). All treatments on a singleplate were measured in multiple wells. Data from all wells with the sametreatment were averaged and the average values were used for analysis.Inhibitory potency of a compound at a single concentration point wasexpressed as percent inhibition of the control agonist response.Sigmoidal concentration-inhibition curves were fitted to the data(derived from at least three independent experiments) and IC₅₀-valueswere determined as the concentration that produces half of the maximalinhibition caused by the compound.

The examined reference compounds measured in functional and bindingtests are the following:

-   1)    4-{2-[(2,2-diphenyl-ethyl)-amino]-5-{-4-[4-[(4-methyl-1-piperazinyl)-carbonyl]-1-piperidinyl]-sulfonyl}-benzoyl}-morfoline    (NVP-SAA164, Br. J. Pharmacol. 144 (2005) 889-899); K_(i) 8 nM;    IC₅₀: 33 nM;-   2)    (R)—N-[2,3-dihydro-2-oxo-5-(2-phenyl-ethyl)-1-propyl-1H-1,4-benzodiazepin-3-yl]-N′-{4-[4-(4-pyridinyl)-1-piperazinyl]-phenyl}-urea    (J. Med. Chem. 46 (2003) 1803-1806); K_(i) 0.59 nM; IC₅₀ 1.9 nM;-   3)    N-[4-(,4′-bipiperidin)-1′-ylphenyl]-N′-[(3R)-2,3-dihydro-5-(4-methyl-phenyl)-2-oxo-1-propyl-1H-1,4-benzodiazepin-3-yl]-urea    (J. Med. Chem. 46 (2003) 1803-1806); K_(i) 13.4 nM; IC₅₀ 64.5 nM

The K_(i) and IC₅₀ data measured by us for the reference compounds arein good agreement with the data given in the literature.

In Table I the most effective compounds of this invention measured infunctional assay are listed.

TABLE I Number of example B1 func. 1.1 ++++ 1.2 ++++ 1.3 ++++ 1.4 ++++1.5 ++++ 1.6 ++++ 1.7 ++++ 1.8 ++++ 1.9 ++++ 1.10 ++++ 1.11 ++++ 1.12++++ 1.13 ++++ 1.21 ++++ 1.22 ++++ 2.2 ++++ 2.3 ++++ 2.4 ++++ 2.5 ++++2.6 ++++ 2.7 ++++ 2.10 +++ 2.15 +++ 2.22 ++++ 2.34 ++++ 3.1 ++++ 3.2++++ 3.3 ++++ 3.4 ++++ 3.5 ++++ 3.6 ++++ 3.7 ++++ 3.8 ++++ 3.9 ++++ 3.10++++ 3.13 ++++ 3.14 ++++ 3.15 ++++ 3.16 ++++ 3.17 ++++ 11.1 ++++ 11.2++++ 11.3 ++++ 11.4 ++++ 11.5 ++++ 11.6 ++++ 11.7 ++++ + IC₅₀ > 0.5 μM++ IC₅₀ is between 0.1 and 0.5 μM +++ IC₅₀ is between 20 and 100 nM ++++IC₅₀ < 20 nMReceptor Binding Assays1. Human Recombinant Bradykinin B1 Receptor Binding

Binding assays were carried out on human recombinant bradykinin)receptors (expressed in CHO cells) according to the Euroscreen TechnicalData Sheet (Cat.No.:ES-091). 20 μg protein/tube was incubated with[3,4-prolyl-3,4-³H(N)]-[Des-Arg¹⁰] Kallidin as radioligand. Non specificbinding was determined in the presence of 10 μM Lys-des-Arg⁹-Bradykinin.The final incubation volume was 250 μl. Samples were incubated for 15min. at 25° C. then were rapidly vacuum filtered through GF/B filterspresoaked for at least 1 h in 0.5% PEI. Radioactivity was determined byliquid scintillation spectroscopy.

In Table II the most effective compounds of this invention measured inbinding assay are listed.

TABLE II Number of example B1 binding 1.1 ++++ 1.2 ++++ 1.3 ++++ 1.4++++ 1.5 ++++ 1.6 ++++ 1.7 ++++ 1.8 ++++ 1.9 ++++ 1.10 ++++ 1.11 ++++1.12 ++++ 1.13 ++++ 1.21 ++++ 1.22 ++++ 2.2 ++++ 2.3 ++++ 2.4 ++++ 2.5++++ 2.6 ++++ 2.7 ++++ 2.10 +++ 2.15 +++ 2.22 ++++ 2.34 ++++ 3.1 ++++3.2 ++++ 3.3 ++++ 3.4 ++++ 3.5 ++++ 3.6 ++++ 3.7 ++++ 3.8 ++++ 3.9 ++++3.10 ++++ 3.13 ++++ 3.14 ++++ 3.15 ++++ 3.16 ++++ 3.17 ++++ 11.1 +++11.2 +++ 11.3 ++++ 11.4 ++++ 11.5 ++++ 11.6 ++++ 11.7 ++++ + K_(i) > 0.5μM ++ K_(i) is between 0.1 and 0.5 μM +++ K_(i) is between 20 and 100 nM++++ K_(i) < 20 nM2. Human Recombinant Bradykinin B2 Receptor Binding

Binding assays were carried out on human recombinant bradykinin2receptors (expressed in CHO cells) according to the Receptor BiologyTechnical Data Sheet (Cat.No.:RBHB2M) with minor modifications. 8.4 μgprotein/tube was incubated with [2,3,-prolyl-3,4-³H(N)]-Bradykinin asradioligand. Non specific binding was determined in the presence of 5 μMbradykinin. The final incubation volume was 200 μl. Samples wereincubated for 90 min. at +4° C. then were rapidly vacuum filteredthrough GF/B filters presoaked for at least 1 h in 0.5% PEI.Radioactivity was determined by liquid scintillation spectroscopy.

The compounds exhibited high affinity and selectivity (>50 fold) for thehuman B1 receptor over the human B2 receptor according to bothfunctional and binding assays.

The synthesis of compounds and pharmaceutical compositions according tothe invention is illustrated by the following not limiting Examples.

Reference Example 1 (4-Methyl-piperazin-1-yl)-piperidin-4-yl-methanonehydrochloride a)4-(4-Methyl-piperazine-1-carbonyl)-piperidine-1-carboxylic acidtert-butyl ester

The solution of 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid(Aldrich) (21.88 g, 95.4 mmol), triethylamine (13.3 mL, 95.4 mmol) andHBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (Advanced Chem. Tech.)] (38.36 g, 101.0 mmol) in drydimethylformamide (100 mL) was stirred at room temperature for fiveminutes before N-methyl-piperazine (10.6 mL, 95.5 mmol) was added. ThepH of the reaction mixture was adjusted to 8 by the addition oftriethylamine, the so obtained mixture was stirred at room temperatureovernight, then concentrated in vacuo. The residue was treated withsaturated sodium hydrogencarbonate solution (350 mL), extracted withethyl acetate (3×250 mL), the combined organic layers were washed withsaturated sodium hydrogencarbonate solution, water and brine, dried oversodium sulfate, filtered and concentrated. The residue was submitted tocolumn chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) asadsorbent, and chloroform:methanol=9:1 as eluent to yield 25.8 g (87%)of the title compound as an oil.

b) (4-Methyl-piperazin-1-yl)-piperidin-4-yl-methanone hydrochloride

A mixture of 4-(4-methyl-piperazine-1-carbonyl)-piperidine-1-carboxylicacid tert-butyl ester (25.8 g, 82.8 mmol), dry dioxane (500 mL) and 6.5N hydrogen chloride in dioxane (275 mL) was stirred at room temperatureovernight, then diluted with diethyl ether and stirred at 0° C. for 1 h.The precipitated crystals were filtered off, washed with diethyl etherand dried to yield 12.44 g (54%) of the title compound. Mp: 305-307° C.(decomposition).

Example 1.14-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamidea) 2,4-Dichloro-1-(2-nitro-phenoxy)-benzene

A mixture of 1-fluoro-2-nitrobenzene (4.8 mL, 45.42 mmol), potassiumcarbonate (13.8 g, 0.1 mol) and 2,4-dichloro-phenol (8.16 g, 50.06 mmol)in dry dimethylformamide (70 mL) was stirred at 100° C. for 2 h. Solidswere filtered off, and the filtrate was concentrated in vacuo. Theresidue was partitioned between diethyl ether and 1N sodium hydroxide,the organic layer was washed with 1N sodium hydroxide, water and brine,dried over sodium sulfate, filtered and concentrated in vacuo to yield11.69 g (91%) of the title compound as a yellowish oil, which solidifieson standing. Mp: 58-59° C. MS (EI) 285.2 (MH⁺). Lit. [Chem. Heterocycl.Compd. (Engl. Transl.) 11 (1975) 1356-1358] Mp: 57-58° C.

b) 2-(2,4-Dichloro-phenoxy)-phenylamine [Chem. Abstr. 84 (1976) 164313q]

To a stirred solution of 2,4-dichloro-1-(2-nitro-phenoxy)-benzene (3.5g, 12.32 mmol) in ethyl acetate (60 mL) stannous chloride dihydrate(13.89 g, 61.6 mmol) was added and the mixture was refluxed for 2 hbefore it was quenched with saturated sodium hydrogencarbonate solution(192 mL). The organic phase was separated and the aqueous phase waswashed several times with ethyl acetate. The combined extracts weredried over sodium sulfate, filtered and concentrated in vacuo to yield3.1 g (99%) of the title compound as a yellowish oil: MS (EI) 255.2(MH⁺).

c) 4-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-benzoic acid

Under an atmosphere of argon to an ice cooled solution of2-(2,4-dichloro-phenoxy)-phenylamine (0.5 g, 1.97 mmol) in dry pyridine(5 mL) 4-chlorosulfonyl benzoic acid (0.45 g, 1.97 mmol) was addedportion-wise. The reaction mixture was stirred at room temperatureovernight. The mixture was evaporated in vacuo, the residue was treatedwith 1N hydrochloric acid (20 mL), and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with 1N hydrochloricacid, water and brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was submitted to flash columnchromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck)and chloroform:methanol:acetic acid=294:6:1 as eluent to yield 0.6 g(70%) of the title compound as a light pink solid, which wascrystallized from diethyl ether-petroleum ether. MS (EI) 439.3 (MH⁺).

d) {4-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The solution of 4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoicacid (8.207 g, 18.7 mmol), triethylamine (5.2 mL, 37.4 mmol) and HBTU(8.24 g, 21.7 mmol) in dry dimethyl formamide (150 mL) was stirred atroom temperature for five minutes before glycine ethyl esterhydrochloride (Aldrich) (2.614 g, 18.7 mmol) was added. The pH of thereaction mixture was adjusted to 8 by the addition of triethylamine, theso obtained mixture was stirred at room temperature overnight, thenconcentrated in vacuo. The residue was treated with saturated sodiumhydrogencarbonate solution (300 mL), the precipitated crystals werefiltered off, washed with water and dried. The crude product waspurified by column chromatography using Kieselgel 60 (0.040-0.063 mm)(Merck) as adsorbent, and n-hexane:ethyl acetate=2:1 as eluent to yield7.68 g (78%) of the title compound. MS (EI) 524 (MH⁺).

e) {4-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid

To a stirred solution of{4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acidethyl ester (7.68 g, 14.67 mmol) in a mixture of tetrahydrofuran (36mL), water (18 mL) and methanol (18 mL) lithium hydroxide monohydrate(3.09 g, 73.64 mmol) was added and the reaction mixture was stirred atroom temperature for 2 h. The mixture was concentrated, the residue wasdissolved in water, acidified with 1M hydrochloric acid, theprecipitated solid was filtered off, washed with water and dried toyield 6.76 g (93%) of the title compound as a yellowish solid. MS (EI)496.2 (MH⁺).

f)4-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide

To a stirred solution of{4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid(42 mg, 0.085 mmol) in a mixture of dichloromethane (2 mL) anddimethylformamide (0.2 mL) 1-(2-pyrrolidin-1-yl-ethyl)-piperazine(EMKA-Chemie) (18 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol) andtriethylamine (60 μL, 0.4 mmol) were added. The mixture was stirred atroom temperature for 24 h, then purified by column chromatography usingKieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and gradient elutionstarting with 100% A eluent and processing to a mixture of 70% A and 30%B eluent over a period of 15 minutes (eluent A: chloroform; eluent B:methanol containing 5% of ammonium hydroxide) to yield 45.8 mg (82%) ofthe title compound. MS (EI) 661.2 (MH⁺).

Compounds of Table 1 were prepared from{4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 1.1/e) according to the method described in Example 1.1/f.

TABLE 1 MS (EI) Example Name (MH⁺) 1.24-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2- 635.2dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 1.34-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2- 663.2diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 1.44-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 675.2(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide 1.54-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(1- 675.2methyl-piperidin-3-ylmethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 1.64-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 660.2(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide 1.74-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4- 642.1pyrimidin-2-yl-piperazin-1-yl)-ethyl]-benzamide 1.84-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3- 705.2morpholin-4-yl-propyl)-[1,4]diazepan-1-yl]-2-oxo-ethyl}- benzamide 1.94-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 689.2(3-piperidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide 1.104-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3- 649.2dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}- benzamide 1.114-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 689.2(3-pyrrolidin-1-yl-propyl)-[1,4]diazepan-1-yl]-ethyl}- benzamide 1.124-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3- 691.2morpholin-4-yl-propyl)-piperazin-1-yl]-2-oxo-ethyl}- benzamide 1.134-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 675.2(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide 1.144-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 675.2(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}- benzamide 1.154-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2- 677.2morpholin-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 1.164-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 689.2(2-oxo-2-piperidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}- benzamide 1.174-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2-{4- 711.2[(methyl-phenyl-carbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-benzamide 1.184-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2- 691.2morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}- benzamide 1.194-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2- 642.2(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-benzamide 1.204-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(4- 689.2methyl-piperazine-1-carbonyl)-piperidin-1-yl]-2-oxo-ethyl}- benzamide1.21 4-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4- 632.2pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-benzamide 1.224-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 579.2hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide 1.234-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2-{4-[2-(2- 652.2hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)- benzamide 1.244-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4- 640.2phenyl-piperazin-1-yl)-ethyl]-benzamide 1.25N-(2-[1,4′]Bipiperidinyl-1′-yl-2-oxo-ethyl)-4-[2-(2,4-dichloro- 646.2phenoxy)-phenylsulfamoyl]-benzamide 1.264-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2- 563.2piperidin-1-yl-ethyl)-benzamide 1.274-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4- 577.1oxo-piperidin-1-yl)-ethyl]-benzamide 1.28N-(2-Azepan-1-yl-2-oxo-ethyl)-4-[2-(2,4-dichloro-phenoxy)- 577.1phenylsulfamoyl]-benzamide 1.294-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2- 549.1pyrrolidin-1-yl-ethyl)-benzamide 1.304-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2- 565.1morpholin-4-yl-2-oxo-ethyl)-benzamide 1.31N-[2-(4-Cyano-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(2,4-dichloro- 588.1phenoxy)-phenylsulfamoyl]-benzamide 1.324-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4- 631.1trifluoromethyl-piperidin-1-yl)-ethyl]-benzamide 1.334-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2- 581.1thiomorpholin-4-yl-ethyl)-benzamide 1.344-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 577.1methyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 1.35N-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-ethyl]-4-[2-(2,4- 668.1dichloro-phenoxy)-phenylsulfamoyl]-benzamide 1.364-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(furan- 658.12-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 1.374-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 656.1ethanesulfonyl-piperazin-1-yl)-2-oxo-ethyl]-benzamide 1.381-(2-{4-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]- 606.1benzoylamino}-acetyl)-piperidine-4-carboxylic acid amide 1.394-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(3- 593.2hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 1.404-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(3- 578.1oxo-piperazin-1-yl)-ethyl]-benzamide 1.414-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 593.1hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 1.424-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2- 607.1hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-benzamide 1.434-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(3- 565.1hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-benzamide 1.44N-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethyl]-4-[2-(2,4-dichloro- 606.1phenoxy)-phenylsulfamoyl]-benzamide 1.454-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 662.1(tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethyl}- benzamide 1.464-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3- 656.1hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 1.474-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(1,1- 613dioxo-1λ⁶-thiomorpholin-4-yl)-2-oxo-ethyl]-benzamide 1.48N-[2-(4-Cyclopropylmethyl-piperazin-1-yl)-2-oxo-ethyl]-4-[2- 618.2(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzamide 1.494-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4-ethyl- 592.1piperazin-1-yl)-2-oxo-ethyl]-benzamide

Example 2.1N-{2-Oxo-2-[(S)-2-(piperazine-1-carbonyl)-pyrrolidin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride a) 4-(2-Phenoxy-phenylsulfamoyl)-benzoic acid

The title compound was prepared from 2-phenoxy-phenylamine (Aldrich)according to the method described in Example 1.1/c. MS (EI) 370.2 (MH⁴).

b) [4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid ethyl ester

The title compound was prepared from4-(2-phenoxy-phenylsulfamoyl)-benzoic acid and glycine ethyl esterhydrochloride (Aldrich) according to the method described in Example1.1/d. MS (EI) 455.2 (MH⁺).

c) [4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid

The title compound was prepared from[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid ethyl esteraccording to the method described in Example 1.1/e. MS (EI) 427.2 (MH⁺).

d)(S)-1-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carboxylicacid benzyl ester

The title compound was prepared from[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid and L-prolinebenzyl ester hydrochloride according to the method described in Example1.1/d. MS (EI) 614.3 (MH⁺).

e)(S)-1-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carboxylicacid

The title compound was prepared from(S)-1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carboxylicacid benzyl ester according to the method described in Example 1.1/e. MS(EI) 524.2 (MH⁺).

f)4-((S)-1-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared from(S)-1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carboxylicacid and piperazine-1-carboxylic acid tert-butyl ester according to themethod described in Example 1.1/d. MS (EI) 714.3 (M+Na⁺).

g)N-{2-Oxo-2-[(S)-2-(piperazine-1-carbonyl)-pyrrolidin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride

To a stirred solution of4-((S)-1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester (0.115 g, 0.166 mmol) in dichloromethane (2 mL) 9M hydrogen chloride in ethanol (0.2 mL) was added. The reaction mixturewas stirred at room temperature for 2 h, then diethyl ether (20 mL) wasadded, the precipitated crystals were filtered, washed with diethylether and dried to yield 0.089 g (89%) of the title compound. MS (EI)592.2 (MH⁺).

Compounds of Table 2 were prepared from[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 2.1/c)according to the method described in Example 1.1/f.

TABLE 2 MS (EI) Example Name (MH⁺) 2.2N-{2-Oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-4-(2-592.2 phenoxy-phenylsulfamoyl)-benzamide 2.3N-{2-[4-(2-Dimethylamino-ethyl)-piperazin-1-yl]-2-oxo- 566.2ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.4N-{2-[4-(2-Diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}- 594.24-(2-phenoxy-phenylsulfamoyl)-benzamide 2.5N-{2-Oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]- 606.2ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.6N-{2-[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-2-oxo- 580.2ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.7N-{2-Oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}- 591.24-(2-phenoxy-phenylsulfamoyl)-benzamide 2.8N-(2-[1,4′]Bipiperidinyl-1′-yl-2-oxo-ethyl)-4-(2-phenoxy- 577.2phenylsulfamoyl)-benzamide 2.9N-[2-Oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-4-(2- 563.2phenoxy-phenylsulfamoyl)-benzamide 2.10N-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 510.2phenylsulfamoyl)-benzamide 2.11N-(2-{4-[2-(2-Hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-2-oxo- 583.2ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.12N-[2-Oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-4-(2-phenoxy- 571.2phenylsulfamoyl)-benzamide 2.13N-(2-Oxo-2-piperidin-1-yl-ethyl)-4-(2-phenoxy- 494.2phenylsulfamoyl)-benzamide 2.14N-{2-[4-(4-Methyl-piperazine-1-carbonyl)-piperidin-1-yl]-2- 620.2oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.151-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}- 537.2piperidine-4-carboxylic acid amide 2.16N-[2-(2-Hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2- 524.2phenoxy-phenylsulfamoyl)-benzamide 2.17N-[2-(3-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 510.2phenylsulfamoyl)-benzamide 2.18N-{2-[2-(2-Hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-4-(2- 538.2phenoxy-phenylsulfamoyl)-benzamide 2.19N-[2-Oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-4-(2-phenoxy- 508.2phenylsulfamoyl)-benzamide 2.20N-[2-(3-Hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2- 524.2phenoxy-phenylsulfamoyl)-benzamide 2.21N-[2-Oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-4-(2-phenoxy- 509.2phenylsulfamoyl)-benzamide 2.22N-[2-(4-Hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2- 524.2phenoxy-phenylsulfamoyl)-benzamide 2.23N-{2-[4-(2-Hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-4-(2- 538.2phenoxy-phenylsulfamoyl)-benzamide 2.24N-(2-Azepan-1-yl-2-oxo-ethyl)-4-(2-phenoxy- 508.2phenylsulfamoyl)-benzamide 2.25N-(2-Oxo-2-pyrrolidin-1-yl-ethyl)-4-(2-phenoxy- 480.2phenylsulfamoyl)-benzamide 2.26N-[2-(3-Hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 496.2phenylsulfamoyl)-benzamide 2.27N-(2-Oxo-2-thiomorpholin-4-yl-ethyl)-4-(2-phenoxy- 512.2phenylsulfamoyl)-benzamide 2.28N-[2-(1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)-2-oxo-ethyl]-4-(2- 544.1phenoxy-phenylsulfamoyl)-benzamide 2.29N-[2-(4-Cyano-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 519.2phenylsulfamoyl)-benzamide 2.30N-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 537.2phenylsulfamoyl)-benzamide 2.31N-{2-Oxo-2-[4-(tetrahydro-furan-2-carbonyl)-piperazin-1-yl]- 593.2ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.32N-{2-[4-(3-Hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4- 587.2(2-phenoxy-phenylsulfamoyl)-benzamide 2.33N-{2-[4-(4-Hydroxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4- 587.2(2-phenoxy-phenylsulfamoyl)-benzamide 2.34N-{2-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo- 592.1ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.35N-[2-(4-Morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl]-4-(2- 579.2phenoxy-phenylsulfamoyl)-benzamide 2.36N-[2-(4-Ethyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 523.2phenylsulfamoyl)-benzamide 2.37N-[2-Oxo-2-(4-phenyl-piperidin-1-yl)-ethyl]-4-(2-phenoxy- 570.2phenylsulfamoyl)-benzamide 2.38N-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 599.2phenylsulfamoyl)-benzamide 2.39N-{2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2- 589.2phenoxy-phenylsulfamoyl)-benzamide 2.40N-{2-[4-(2-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2- 589.2phenoxy-phenylsulfamoyl)-benzamide 2.41N-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2- 589.2phenoxy-phenylsulfamoyl)-benzamide 2.42N-[2-Oxo-2-(4-phenethyl-piperazin-1-yl)-ethyl]-4-(2-phenoxy- 599.2phenylsulfamoyl)-benzamide 2.43N-[2-(4-Cyclopropylmethyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2- 549.2phenoxy-phenylsulfamoyl)-benzamide 2.44N-{2-Oxo-2-[4-(tetrahydro-furan-2-ylmethyl)-piperazin-1-yl]- 579.2ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.45N-[2-(4-Cyclohexyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2- 577.2phenoxy-phenylsulfamoyl)-benzamide 2.46N-{2-[4-(4-Cyano-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2- 596.2phenoxy-phenylsulfamoyl)-benzamide 2.47N-[2-(4-Ethanesulfonyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2- 587.2phenoxy-phenylsulfamoyl)-benzamide 2.48N-{2-[4-(2-Cyano-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2- 596.2phenoxy-phenylsulfamoyl)-benzamide 2.49N-[2-(4-Cyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-4-(2- 591.2phenoxy-phenylsulfamoyl)-benzamide 2.50N-[2-(Octahydro-isoquinolin-2-yl)-2-oxo-ethyl]-4-(2-phenoxy- 548.2phenylsulfamoyl)-benzamide 2.51(1-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}- 566.2piperidin-4-yl)-acetic acid methyl ester 2.52N-{2-Oxo-2-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]- 619.3ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.53N-[2-(4-Cyanomethyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2- 533.2phenoxy-phenylsulfamoyl)-benzamide 2.54N-(2-Morpholin-4-yl-2-oxo-ethyl)-4-(2-phenoxy- 496.1phenylsulfamoyl)-benzamide 2.55N-[2-(4,4-Difluoro-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 530.2phenylsulfamoyl)-benzamide 2.56N-[2-(4-Methyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 508.2phenylsulfamoyl)-benzamide 2.571-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}- 581.2piperidine-4-carboxylic acid (2-hydroxy-ethyl)-amide 2.58N-[2-(4-Acetylamino-piperidin-1-yl)-2-oxo-ethyl]-4-(2- 551.2phenoxy-phenylsulfamoyl)-benzamide 2.59N-[2-(4-Methanesulfonylamino-piperidin-1-yl)-2-oxo-ethyl]-4- 587.2(2-phenoxy-phenylsulfamoyl)-benzamide 2.601-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}- 633.2piperidine-4-carboxylic acid cycloheptylamide 2.61N-[2-((S)-5-Benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-oxo- 597.2ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide 2.621-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}- 565.4piperidine-4-carboxylic acid dimethylamid 2.63N-[2-(4-Methoxy-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy- 524.4phenylsulfamoyl)-benzamide 2.641-{2-[4-(2-Phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}- 593.4piperidine-4-carboxylic acid tert-butylamide 2.65N-(2-Azocan-1-yl-2-oxo-ethyl)-4-(2-phenoxy- 522.4phenylsulfamoyl)-benzamide

Example 3.14-(2-Benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamidea) 4-(2-Benzoyl-phenylsulfamoyl)-benzoic acid

The title compound was prepared from 2-amino-benzophenone according tothe method described in Example 1.1/c. MS (EI) 382.2 (MH⁺).

b) [4-(2-Benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid ethyl ester

The title compound was prepared from4-(2-benzoyl-phenylsulfamoyl)-benzoic acid and glycine ethyl esterhydrochloride (Aldrich) according to the method described in Example1.1/d. MS (EI) 867.2 (MH⁺).

c) [4-(2-Benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid

The title compound was prepared from[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid ethyl esteraccording to the method described in Example 1.1/e. MS (EI) 439.2 (MH⁺).

d)4-(2-Benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide

The title compound was prepared from[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid and1-(2-pyrrolidin-1-yl-ethyl)-piperazine (EMKA-Chemie) according to themethod described in Example 1.1/f. MS (EI) 604.2 (MH⁺).

Compounds of Table 3 were prepared from[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 3.1/c)according to the method described in Example 1.1/f.

TABLE 3 MS (EI) Example Name (MH⁺) 3.24-(2-Benzoyl-phenylsulfamoyl)-N-{2-[4-(2-dimethylamino- 578.2ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 3.34-(2-Benzoyl-phenylsulfamoyl)-N-(2-oxo-2-piperidin-1-yl-ethyl)- 506.2benzamide 3.4 N-(2-Azepan-1-yl-2-oxo-ethyl)-4-(2-benzoyl- 520.2phenylsulfamoyl)-benzamide 3.54-(2-Benzoyl-phenylsulfamoyl)-N-[2-(4-cyano-piperidin-1-yl)- 531.22-oxo-ethyl]-benzamide 3.64-(2-Benzoyl-phenylsulfamoyl)-N-[2-oxo-2-(4-trifluoromethyl- 574.2piperidin-1-yl)-ethyl]-benzamide 3.74-(2-Benzoyl-phenylsulfamoyl)-N-[2-(4-methyl-piperidin-1- 520.2yl)-2-oxo-ethyl]-benzamide 3.84-(2-Benzoyl-phenylsulfamoyl)-N-{2-[4-(1-methyl-piperidin-3- 618.2ylmethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 3.94-(2-Benzoyl-phenylsulfamoyl)-N-[2-(4-hydroxymethyl- 536.2piperidin-1-yl)-2-oxo-ethyl]-benzamide 3.104-(2-Benzoyl-phenylsulfamoyl)-N-{2-[4-(2-hydroxy-ethyl)- 550.2piperidin-1-yl]-2-oxo-ethyl}-benzamide 3.114-(2-Benzoyl-phenylsulfamoyl)-N-(2-oxo-2-pyrrolidin-1-yl- 492.2ethyl)-benzamide 3.124-(2-Benzoyl-phenylsulfamoyl)-N-[2-(3-hydroxy-pyrrolidin-1- 508.2yl)-2-oxo-ethyl]-benzamide 3.134-(2-Benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(3-pyrrolidin-1- 618.2yl-propyl)-piperazin-1-yl]-ethyl}-benzamide 3.144-(2-Benzoyl-phenylsulfamoyl)-N-{2-[4-(3-dimethylamino- 592.2propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide 3.154-(2-Benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1- 603.2yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide 3.164-(2-Benzoyl-phenylsulfamoyl)-N-[2-(4-hydroxy-piperidin-1- 522.2yl)-2-oxo-ethyl]-benzamide 3.171-{2-[4-(2-Benzoyl-phenylsulfamoyl)-benzoylamino]-acetyl}- 549.2piperidine-4-carboxylic acid amide 3.184-(2-Benzoyl-phenylsulfamoyl)-N-(2-morpholin-4-yl-2-oxo- 508.2ethyl)-benzamide 3.194-(2-Benzoyl-phenylsulfamoyl)-N-[2-oxo-2-(3-oxo-piperazin- 521.21-yl)-ethyl]-benzamide 3.204-(2-Benzoyl-phenylsulfamoyl)-N-(2-oxo-2-thiomorpholin-4- 524.2yl-ethyl)-benzamide 3.214-(2-Benzoyl-phenylsulfamoyl)-N-[2-(1,1-dioxo-1λ⁶- 556.1thiomorpholin-4-yl)-2-oxo-ethyl]-benzamide 3.224-(2-Benzoyl-phenylsulfamoyl)-N-[2-(3-hydroxymethyl- 536.2piperidin-1-yl)-2-oxo-ethyl]-benzamide 3.234-(2-Benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(3-pyrrolidin-1- 632.5yl-propyl)-[1,4]diazepan-1-yl]-ethyl}-benzamide 3.244-(2-Benzoyl-phenylsulfamoyl)-N-[2-oxo-2-(4-oxo-piperidin-1- 520.3yl)-ethyl]-benzamide

Example 4.14-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperidin-1-yl-ethyl)-benzamidea) 4-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from5-fluoro-2-(4-fluoro-phenoxy)-phenylamine [Yakugaku Zasshi; 88 (1968)1361, 1365; Chem. Abstr.; 70 (1969) 68312] according to the methoddescribed in Example 1.1/c. MS (EI) 406.3 (MH⁺).

b){4-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The title compound was prepared from4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid andglycine ethyl ester hydrochloride (Aldrich) according to the methoddescribed in Example 1.1/d.

c){4-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid

The title compound was prepared from{4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester according to the method described in Example 1.1/e. MS(EI) 463.1 (MH⁺).

d)4-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperidin-1-yl-ethyl)-benzamide

The title compound was prepared from{4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid and piperidine according to the method described in Example 1.1/f.MS (EI) 533.3 (MH⁺).

Compounds of Table 4 were prepared from{4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 4.1/c) according to the method described in Example 1.1/f.

TABLE 4 MS (EI) Example Name (MH⁺) 4.2N-(2-Azepan-1-yl-2-oxo-ethyl)-4-[5-fluoro-2-(4-fluoro- 544.4phenoxy)-phenylsulfamoyl]-benzamide 4.34-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 546.3hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide 4.44-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 560.3hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 4.54-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-[4- 574.4(2-hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-benzamide 4.64-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-oxo- 607.42-(4-phenyl-piperazin-1-yl)-ethyl]-benzamide 4.74-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 627.5(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide

Example 5.14-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamidea) 2-Chloro-4-fluoro-1-(2-nitro-phenoxy)-benzene

The title compound was prepared from 2-chloro-4-fluoro-phenol accordingto the method described in Example 1.1/a.

b) 2-(2-Chloro-4-fluoro-phenoxy)-phenylamine

The title compound was prepared from2-chloro-4-fluoro-1-(2-nitro-phenoxy)-benzene according to the methoddescribed in Example 1.1/b.

c) 4-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from2-(2-chloro-4-fluoro-phenoxy)-phenylamine according to the methoddescribed in Example 1.1/c. MS (EI) 422.1 (MH⁺).

d){4-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The title compound was prepared from4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid andglycine ethyl ester hydrochloride according to the method described inExample 1.1/d.

e){4-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid

The title compound was prepared from{4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester according to the method described in Example 1.1/e. MS(EI) 479 (MH⁺).

f)4-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide

The title compound was prepared from{4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid and 4-hydroxypiperidine according to the method described inExample 1.1/f. MS (EI) 562.3 (MH⁺).

Compounds of Table 5 were prepared from{4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 5.1/e) according to the method described in Example 1.1/f.

TABLE 5 MS (EI) Example Name (MH⁺) 5.24-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-oxo- 644.42-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide 5.34-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4- 658.5(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide 5.44-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-oxo- 643.42-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide 5.54-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 576.3hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 5.61-(2-{4-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]- 589.3benzoylamino}-acetyl)-piperidine-4-carboxylic acid amide 5.74-[2-(2-Chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-[4- 644.4(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}- benzamide

Example 6.14-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamidea) 4-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from(2-amino-phenyl)-(2,4-dichloro-phenyl)-methanone [Synthesis, (1980)677-688] and 4-chlorosulfonyl-benzoic acid according to the methoddescribed in Example 1.1/c. MS (EI) 451 (MH⁺).

b) {4-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The title compound was prepared from4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoic acid and glycineethyl ester hydrochloride according to the method described in Example1.1/d. MS (EI) 536.1 (MH⁺).

c) {4-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-aceticacid

The title compound was prepared from{4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acidethyl ester according to the method described in Example 1.1/e. MS (EI)508 (MH⁺).

d)4-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide

The title compound was prepared from{4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acidand 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (EMKA-Chemie) according tothe method described in Example 1.1/f. MS (EI) 673.2 (MH⁺).

Compounds of Table 6 were prepared from{4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 6.1/c) according to the method described in Example 1.1/f.

TABLE 6 MS (EI) Example Name (MH⁺) 6.24-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2-oxo-2-[4- 701.4(3-piperidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide 6.34-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2-oxo-2-[4- 687.2(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide 6.44-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2-[4-(3- 661.4dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}- benzamide 6.54-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2-oxo-2-[4- 672.4(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide 6.64-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-[2-(4- 591.2hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide 6.74-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-[2-(4- 605.2hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 6.81-(2-{4-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]- 618.3benzoylamino}-acetyl)-piperidine-4-carboxylic acid amide 6.94-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-{2- 673.4[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide

Example 7.14-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamidea) 4-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from 2-(4-fluoro-phenoxy)-phenylamine[Helv. Chim. Acta; 48 (1965) 336-347] according to the method describedin Example 1.1/c. MS (EI) 388.2 (MH⁺).

b) {4-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acidethyl ester

The title compound was prepared from4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethylester hydrochloride according to the method described in Example 1.1/d.

c) {4-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid

The title compound was prepared from{4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acidethyl ester according to the method described in Example 1.1/e. MS (EI)445.1 (MH⁴).

d)4-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide

The title compound was prepared from{4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and4-hydroxypiperidine according to the method described in Example 1.1/f.MS (EI) 528.4 (MH⁺).

Compounds of Table 7 were prepared from{4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]benzoylamino}-acetic acid(Example 7.1/c) according to the method described in Example 1.1/f.

TABLE 7 MS (EI) Example Name (MH⁺) 7.24-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]- 512.3N-(2-oxo-2-piperidin-1-yl-ethyl)-benzamide 7.34-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 542.4hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]- benzamide 7.44-[2-(4-Fluoro-phenoxy)-phenylsulfamoyl]-N-{2- 556.2[4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-oxo- ethyl}-benzamide

Example 8.1N-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(4-trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzamidea) 4-[2-(4-Trifluormethyl-phenoxy)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from2-(4-trifluoromethyl-phenoxy)-phenylamine [J. Chem. Soc. PerkinTrans. 1. (1976) 1279-1285] according to the method described in Example1.1/c. MS (EI) 438.0 (MH⁺).

b){4-[2-(4-Trifluormethyl-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The title compound was prepared from4-[2-(4-trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzoic acid andglycine ethyl ester hydrochloride according to the method described inExample 1.1/d.

c){4-[2-(4-Trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid

The title compound was prepared from{4-[2-(4-trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester according to the method described in Example 1.1/e. MS(EI) 475.2 (MH⁺).

d)N-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(4-trifluoromethyl-phenoxy)-phenylsulfamoyl]-benzamide

The title compound was prepared from{4-[2-(4-trifuormethyl-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid and 4-hydroxypiperidine according to the method described inExample 1.1/f. MS (EI) 578.3 (MH⁺).

Example 9.1N-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzamidea) 4-[2-(4-Trifluormethoxy-phenoxy)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from2-(4-trifluoromethoxy-phenoxy)-phenylamine [J. Med. Chem. 13 (1970)295-297] according to method described in Example 1.1/c. MS (EI) 454.1(MH⁺).

b){4-[2-(4-Trifluormethoxy-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The title compound was prepared from4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzoic acid andglycine ethyl ester hydrochloride according to the method described inExample 1.1/d.

c){4-[2-(4-Trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid

The title compound was prepared from{4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester according to the method described in Example 1.1/e. MS(EI) 511 (MH⁺).

d)N-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzamide

The title compound was prepared from{4-[2-(4-trifuormethoxy-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid and 4-hydroxypiperidine according to the method described inExample 1.1/f. MS (EI) 594.3 (MH⁺).

Compounds of Table 9 were prepared from{4-[2-(4-trifluormethoxy-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 9.1/c) according to the method described in Example 1.1/f.

TABLE 9 MS (EI) Example Name (MH⁺) 9.2N-{2-Oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)- 676.5piperazin-1-yl]-ethyl}-4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzamide 9.3N-{2-[4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]- 676.52-oxo-ethyl}-4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzamide

Example 10.14-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamidea) 4-Bromo-2-chloro-1-(2-nitro-phenoxy)-benzene

The title compound was prepared from 4-bromo-2-chloro-phenol accordingto the method described in Example 1.1/a. MS (EI) 329.3 (MH⁺).

b) 2-(4-Bromo-2-chloro-phenoxy)-phenylamine

The title compound was prepared from4-bromo-2-chloro-1-(2-nitro-phenoxy)-benzene according to the methoddescribed in Example 1.1/b. MS (EI) 300.2 (MH⁺).

c) 4-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoic acid

The title compound was prepared from2-(4-bromo-2-chloro-phenoxy)-phenylamine according to the methoddescribed in Example 1.1/c. MS (EI) 483.4 (MH⁺).

d){4-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester

The title compound was prepared from4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoic acid andglycine ethyl ester hydrochloride according to the method described inExample 1.1/d.

e){4-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid

The title compound was prepared from{4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid ethyl ester according to the method described in Example 1.1/e. MS(EI) 541.1 (MH⁺).

f)4-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide

The title compound was prepared from{4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid and 4-hydroxypiperidine according to the method described inExample 1.1/f. MS (EI) 623.3 (MH⁺).

Compounds of Table 10 were prepared from{4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 10.1/e) according to the method described in Example1.1/f.

TABLE 10 MS (EI) Example Name (MH⁺) 10.24-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo- 705.42-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide 10.34-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo- 720.42-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}- benzamide 10.44-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo- 705.42-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide 10.51-(2-{4-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]- 651.3benzoylamino}-acetyl)-piperidine-4-carboxylic acid amide 10.64-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-[2-(4- 638.3hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide 10.74-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-{2-[4- 706.4(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide

Example 11.1N-(2-[1,4]-Diazepan-1-yl-2-oxo-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride

To a stirred solution of[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 2.1/c)(36 mg, 0.085 mmol) in a mixture of dichloromethane (2 mL) anddimethylformamide (0.2 mL) and [1,4]diazepane-1-carboxylic acidtert-butyl ester (Fluka) (20 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol) andtriethylamine (30 μL, 0.2 mmol) were added. The mixture was stirred atroom temperature for 24 h, then purified by column chromatography usingKieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and gradient elutionstarting with 100% A eluent and processing to 100% B eluent over aperiod of 20 minutes (eluent A: n-hexane; eluent B: ethyl acetate). Thepurified compound was dissolved in ethyl acetate (0.5 mL) 2.5 M hydrogenchloride in ethyl acetate (2.0 mL) was added and the mixture was stirredat room temperature for 24 h. The precipitated product was filtered,washed with diethyl ether and dried in vacuum to yield 29 mg (62%) ofthe title compound. MS (EI) 509.2 (MH⁺).

Example 11.2N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamidehyrochloride

The title compound was prepared from[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 2.1/c)and piperazine-1-carboxylic acid tert-butyl ester (Aldrich) according tothe method described in Example 11.1. MS (EI) 495.2 (MH⁺).

Example 11.3N-[2-(4-Amino-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride

The title compound was prepared from[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 2.1/c)and piperidin-4-yl-carbamic acid tert-butyl ester (Aldrich) according tothe method described in Example 11.1. MS (EI) 509.0 (MH⁺).

Example 11.44-[2-(2,4-Dichloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride

The title compound was prepared from{4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 1.1/e) and piperazine-1-carboxylic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)564.2 (MH⁺).

Example 11.5N-(2-[1,4]Diazepan-1-yl-2-oxo-ethyl)-4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzamidehydrochloride

The title compound was prepared from{4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 1.1/e) and [1,4]diazepane-1-carboxylic acid tert-butyl ester(Fluka) according to the method described in Example 11.1. MS (EI) 578.2(MH⁺).

Example 11.64-(2-Benzoyl-phenylsulfamoyl)-N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-benzamidehydrochloride

The title compound was prepared from[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 3.1/c)and [1,4]diazepane-1-carboxylic acid tert-butyl ester (Fluka) accordingto the method described in Example 11.1. MS (EI) 521.2 (MH⁺).

Example 11.74-(2-Benzoyl-phenylsulfamoyl)-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride

The title compound was prepared from[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 3.1/c)and piperazine-1-carboxylic acid tert-butyl ester (Aldrich) according tothe method described in Example 11.1. MS (EI) 507.2 (MH⁺).

Example 11.8N-[2-(4-Amino-piperidin-1-yl)-2-oxo-ethyl]-4-(2-benzoyl-phenylsulfamoyl)-benzamidehydrochloride

The title compound was prepared from[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 3.1/c)and piperidin-4-yl-carbamic acid tert-butyl ester (Aldrich) according tothe method described in Example 11.1. MS (EI) 521.2 (MH⁺).

Example 11.9N-[2-(4-Amino-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzamidehydrochloride

The title compound was prepared from{4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 1.1/e) and piperidin-4-yl-carbamic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)577.2 (MH^(±)).

Example 11.104-[5-Fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride

The title compound was prepared from{4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 4.1/c) and piperazine-1-carboxylic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)531.2 (MH⁺).

Example 11.11N-(2-[1,4]Diazepan-1-yl-2-oxo-ethyl)-4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzamidehydrochloride

The title compound was prepared from{4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 6.1/c)) and [1,4]diazepane-1-carboxylic acid tert-butyl ester(Fluka) according to the method described in Example 11.1. MS (EI) 589.3(MH⁺).

Example 11.124-[2-(2,4-Dichloro-benzoyl)-phenylsulfamoyl]-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride

The title compound was prepared from{4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 6.1/c)) and piperazine-1-carboxylic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)575.3 (MH⁺).

Example 11.13N-[2-(4-Amino-piperidin-1-yl)-2-oxo-ethyl]-4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzamidehydrochloride

The title compound was prepared from{4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid(Example 6.1/c)) and piperidin-4-yl-carbamic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)589.3 (MH⁺).

Example 11.14N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-[2-(4-trifluoromethoxy-phenoxy)-phenylsulfamoyl]-benzamidehydrochloride

The title compound was prepared from{4-[2-(4-trifluormethoxy-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 9.1/c) and piperazine-1-carboxylic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)579.3 (MH⁺).

Example 11.154-[2-(4-Bromo-2-chloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride

The title compound was prepared from{4-[2-(4-bromo-2-chloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-aceticacid (Example 10.1/e) and piperazine-1-carboxylic acid tert-butyl ester(Aldrich) according to the method described in Example 11.1. MS (EI)609.2 (MH⁺).

Example 12N-((S)-2-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-2-oxo-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamide

A stirred mixture ofN-[2-((S)-5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide(Example 2.61) (46 mg, 0.077 mmol) and 10% Pd/C (10 mg) in acetic acid(5 mL) was hydrogenated at 5 bar at room temperature for 2 h. Thecatalyst was filtered off and the filtrate was concentrated in vacuo.The residue was purified by column chromatography using Kieselgel 60(0.015-0.040 mm) (Merck) as adsorbent and chloroform:methanol:ammoniumhydroxide=9:1:0.1 as eluent to yield 37.9 mg (97%) of the titlecompound. MS (EI) 507.1 (MH⁺).

Example 13 Preparation of Pharmaceutical Compositions

a) Tablets:

0.01-50% of active ingredient of formula (I), 15-50% of lactose, 15-50%of potato starch, 5-15% of polyvinyl pyrrolidone, 1-5% of talc, 0.01-3%of magnesium stearate, 1-3% of colloid silicon dioxide and 2-7% ofultraamylopectin were mixed, then granulated by wet granulation andpressed to tablets.

b) Dragées, Filmcoated Tablets:

The tablets made according to the method described above were coated bya layer consisting of entero- or gastrosolvent film, or of sugar andtalc. The dragées were polished by a mixture of beeswax and carnuba wax.

c) Capsules:

0.01-50% of active ingredient of formula (I), 1-5% of sodium laurylsulfate, 15-50% of starch, 15-50% of lactose, 1-3% of colloid silicondioxide and 0.01-3% of magnesium stearate were thoroughly mixed, themixture was passed through a sieve and filled in hard gelatin capsules.

d) Suspensions:

Ingredients: 0.01-15% of active ingredient of formula (I), 0.1-2% ofsodium hydroxide, 0.1-3% of citric acid, 0.05-0.2% of nipagin (sodiummethyl 4-hydroxybenzoate), 0.005-0.02% of nipasol, 0.01-0.5% of carbopol(polyacrilic acid), 0.1-5% of 96% ethanol, 0.1-1% of flavoring agent,20-70% of sorbitol (70% aqueous solution) and 30-50% of distilled water.

To solution of nipagin and citric acid in 20 ml of distilled water,carbopol was added in small portions under vigorous stirring, and thesolution was left to stand for 10-12 h. Then the sodium hydroxide in 1ml of distilled water, the aqueous solution of sorbitol and finally theethanolic raspberry flavor were added with stirring. To this carrier theactive ingredient was added in small portions and suspended with animmersing homogenizator. Finally the suspension was filled up to thedesired final volume with distilled water and the suspension syrup waspassed through a colloid milling equipment.

e) Suppositories:

For each suppository 0.01-15% of active ingredient of formula (I) and1-20% of lactose were thoroughly mixed, then 50-95% of adeps prosuppository (for example Witepsol 4) was melted, cooled to 35° C. andthe mixture of active ingredient and lactose was mixed in it withhomogenizator. The obtained mixture was mould in cooled forms.

f) Lyophilized Powder Ampoule Compositions:

A 5% solution of mannitol or lactose was made with bidistilled water forinjection use, and the solution was filtered so as to have sterilesolution. A 0.01-5% solution of the active ingredient of formula (I) wasalso made with bidistilled water for injection use, and this solutionwas filtered so as to have sterile solution. These two solutions weremixed under aseptic conditions, filled in 1 ml portions into ampoules,the content of the ampoules was lyophilized, and the ampoules weresealed under nitrogen. The contents of the ampoules were dissolved insterile water or 0.9% (physiological) sterile aqueous sodium chloridesolution before administration.

The invention claimed is:
 1. A compound of formula (I)

wherein R¹ is selected from a hydrogen atom and C₁-C₄ alkyl group; R² isselected from (1) a hydrogen atom; (2) C₁-C₆ alkyl group, said C₁-C₆alkyl group is straight or branched; (3) —(CH₂)_(n)—NH₂; (4)—(CH₂)_(n)—OH; (5) —(CH₂)_(n)—CO—NH₂; (6) —(CH₂)_(n)—COOR^(c); and (7)benzyl, said benzyl is optionally substituted with one or more hydroxygroup or halogen atom; or R¹, R² and the carbon atom to which they areboth attached together form a 3-7 membered cycloalkyl ring; R³, R⁴ andR⁵ are independently of each other selected from: a hydrogen atom;halogen atom; cyano; nitro; amino; amino substituted with one or moreC₁-C₄ alkyl group; trifluoromethyl; C₁-C₄ alkyl; C₁-C₄ alkoxy;trifluoromethoxy; C₁-C₄ alkoxycarbonyl; —C(═O)—NH₂; and hydroxy group; Zis selected from (1) single bond; (2) oxygen atom; (3) CH₂ group; (4) COgroup; (5) NR^(c) group; (6) S atom; and (7) SO₂ group; Q is selectedfrom

optionally substituted with —(CH₂)_(m)—OH group or —(CH₂)_(n)—X—P group;

optionally substituted with one or more C₁-C₄ alkyl group, one or morehalogen atom, —(CH₂)_(m)—OH group, —(CH₂)_(m)—NH₂ group,—(CH₂)_(m)—CO—NH₂ group, trifluoromethyl group, oxo group, —(CH₂)_(m)—CNgroup, —NH—CO—(C₁-C₄ alkyl) group, —NH—SO₂—(C₁-C₄ alkyl) group,—(CH₂)_(m)—COOR^(c) group, —CO—NR^(c)R^(d) group, —(C₁-C₄ alkoxy) group,—NH—CO—(CH₂)_(m)—CF₃ group, or —NH—SO₂—CH₂—CF₃ group;

group;

optionally substituted with an oxo group, —SO₂—(C₁-C₄ alkyl) group,C₁-C₄ alkyl group, —CO—(C₁-C₄ alkyl) group, —(CH₂)_(m)—O—(CH₂)_(m)—OHgroup, —(CH₂)_(m)—OH group, —SO₂—NR^(c)R^(d) group, or —CO—NR^(c)R^(d)group;

group;

group;

group;

optionally substituted with —(CH₂)_(m)—OH group,

group;

group; and,

group; Y is selected from (1) —(CH₂)_(n)—NR^(a)R^(b); and, (2)—(CH₂)_(n)—X—P group; n is an integer from 0 to 6; m is an integer from0 to 3; X is selected from (1) single bond; (2) oxygen atom; (3)—CO—NR^(c) group; (4) CO; and (5) SO₂ group; P is selected from (1)phenyl group, optionally substituted with one or more halogen atom,hydroxy, cyano, amino or C₁-C₄ alkyl group; (2) a 4-7 membered ringcontaining 1-3 heteroatom selected from O, S, SO₂ and N, said 4-7membered ring is saturated, partially unsaturated, or aromatic, and said4-7 membered ring is optionally substituted with one or more halogenatom, oxo, hydroxy, cyano, amino or C₁-C₄ alkyl group; and, (3) C₅-C₈cycloalkyl group; R^(a) and R^(b) are independently of each otherselected from (1) hydrogen atom, and (2) C₁-C₆ alkyl group, said C₁-C₆alkyl group is straight or branched, with the proviso that Ra and Rb cannot be simultaneously hydrogen atom; or R^(a), R^(b) and the nitrogenatom to which they are both attached together form a saturated,partially unsaturated or aromatic 4-7 membered ring containing 0-3heteroatom (in addition to the nitrogen atom to which R^(a) and R^(b)attached) selected from O, S, SO₂ and N; wherein said ring is optionallysubstituted with one or more halogen atom, oxo, cyano, hydroxy or C₁-C₄alkyl group; R^(c) is selected from a hydrogen atom and C₁-C₄ alkylgroup; R^(d) is selected from a hydrogen atom, C₁-C₄ alkyl group, C₁-C₄hydroxyalkyl group, and C₃-C₈ cycloalkyl group; R^(e) is selected from ahydrogen atom, C₁-C₄ alkyl group, and benzyl group; A is selected from(1) a C₄-C₇ cycloalkyl ring; and (2) a 5-7 membered ring containing 0-3heteroatom selected from O, S, SO₂ and N, and wherein said ring issaturated, partially unsaturated or aromatic, and is optionallysubstituted with one or more halogen atom, oxo, cyano, hydroxy, amino,phenyl or C₁-C₄ alkyl group; B is selected from a 4-7 membered ringcontaining 1-3 heteroatom selected from O, S, SO₂ and N; wherein saidring saturated, partially unsaturated or aromatic, and is optionallysubstituted with one or more halogen atom, oxo, cyano, hydroxy, amino,phenyl or C₁-C₄ alkyl group; W¹ is selected from a carbon atom, nitrogenatom, and CH group; and, W² is selected from an oxygen atom, sulfuratom, NH, CH₂ and SO₂ group.
 2. A compound according to claim 1, whereinthe compound is in the form of a pharmaceutically-acceptable salt.
 3. Acompound according to claim 1, wherein the compound is in the form of ahydrate.
 4. A compound according to claim 1, wherein the compound is inthe form of a solvate.
 5. A compound according to claim 1, wherein thecompound is optically active.
 6. A racemic mixture of compoundsaccording to claim
 5. 7. A compound according to claim 1, wherein thecompound is selected from4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(1-methyl-piperidin-3-ylmethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3-morpholin-4-yl-propyl)-[1,4]diazepan-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(3-piperidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-[1,4]diazepan-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3-morpholin-4-yl-propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide;N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide;1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-piperidine-4-carboxylicacid amide;N-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride;N-(2-oxo-2-piperazin-1-yl-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamidehyrochlorid;N-[2-(4-amino-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride;N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzamidehydrochloride;4-(2-benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-(2-oxo-2-piperidin-1-yl-ethyl)-benzamide;N-(2-azepan-1-yl-2-oxo-ethyl)-4-(2-benzoyl-phenylsulfamoyl)-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-cyano-piperidin-1-yl)-2-oxo-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-oxo-2-(4-trifluoromethyl-piperidin-1-yl)-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(1-methyl-piperidin-3-ylmethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide;1-{2-[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetyl}-piperidine-4-carboxylicacid amide;4-(2-benzoyl-phenylsulfamoyl)-N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-benzamidehydrochloride; and,4-(2-benzoyl-phenylsulfamoyl)-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride.
 8. A process for preparing a compound of formula (I) inaccordance with claim 1, comprising: (a) reacting an amine derivative offormula (II),

wherein the meaning of R³, R⁴ and R⁵ is as described above for theformula (I), with a sulfonyl chloride of formula (III)

to obtain a compound of formula (IV),

wherein the meaning of R³, R⁴ and R⁵ is as described above for theformula (I); (b) reacting the compound of formula (IV) with an aminoacid of formula (V),

wherein the meaning of R¹ and R² is as described above for the formula(I) and R is C₁-C₄ alkyl group, to obtain a compound of formula (VI),

wherein the meaning of R¹, R², R³, R⁴, R⁵ and R is as defined above; (c)hydrolyzing the compound of formula (VI) to furnish an acid derivativeof formula (VII),

wherein the meaning of R¹, R², R³, R⁴ and R⁵ is as defined above; and,(d) reacting the acid derivative of formula (VII) with an aminederivative H-Q, wherein Q is as described in formula (I), resulting in abenzamide derivative of formula (I).
 9. A process according to claim 8,wherein the process comprises preparing an optical antipode, racemate,solvate, hydrate, or pharmaceutically-acceptable salt of thephenylsulfamoyl benzamide derivative of formula (I).
 10. A process forpreparing a compound of formula (I) in accordance with claim 1,comprising transforming a compound of formula (I) into an other compoundof formula (I) by one or more of: introducing new substituents;modifying or removing existing substituents; salt formation; orliberating a compound from a salt.
 11. A pharmaceutical compositioncomprising a compound of formula (I) in accordance with claim 1 and oneor more pharmaceutically acceptable excipients.
 12. A compound offormula (I)

wherein R¹ is hydrogen atom or C₁-C₄ alkyl group; R² is selected from(1) hydrogen atom; (2) C₁-C₆ straight or branched alkyl group; (3)—(CH₂)_(n)—NH₂; (4) —(CH₂)_(n)—OH; (5) —(CH₂)_(n)—CO—NH₂; (6)—(CH₂)_(n)—COOR^(c)(7) benzyl optionally substituted with one or morehydroxy group or halogen atom; or R¹, R² and the carbon atom to whichthey are both attached together form a 3-7 membered cycloalkyl ring; R³,R⁴ and R⁵ are independently of each other hydrogen atom; halogen atom;cyano; nitro; amino; or amino substituted with one or more C₁-C₄ alkylgroup; trifluoromethyl; C₁-C₄ alkyl; C₁-C₄ alkoxy; trifluoromethoxy;C₁-C₄ alkoxycarbonyl; —C(═O)—NH₂ or hydroxy group; Z is selected from(1) single bond; (2) oxygen atom; (3) CH₂ group; (4) CO group; (5)NR^(c) group; (6) S atom; (7) SO₂ group; Q is selected from

optionally substituted with —(CH₂)_(m)—OH group, or —(CH₂)_(n)—X—Pgroup;

optionally substituted with one or more C₁-C₄ alkyl group, one or morehalogen atom, —(CH₂)_(m)—OH group, —(CH₂)_(m)—NH₂ group,—(CH₂)_(m)—CO—NH₂ group, trifluoromethyl group, oxo group, —(CH₂)_(m)—CNgroup; —NH—CO—(C₁-C₄ alkyl) group, —NH—SO₂—(C₁-C₄ alkyl) group,—(CH₂)_(m)—COOR^(c) group, —CO—NR^(c)R^(d) group, —(C₁-C₄ alkoxy) group,—NH—CO—(CH₂)_(m)—CF₃ group, —NH—SO₂—CH₂—CF₃ group;

group;

optionally substituted with oxo group, —SO₂—(C₁-C₄ alkyl) group, C₁-C₄alkyl group, —CO—(C₁-C₄ alkyl) group, —(CH₂)_(m)—O—(CH₂)_(m)—OH group,—(CH₂)_(m)—OH group, —SO₂—NR^(c)R^(d) group, —CO—NR^(c)R^(d) group;

group;

group;

group;

optionally substituted with —(CH₂)_(m)—OH group,

group;

group;

group; Y is selected from (1) —(CH₂)_(n)—NR^(a)R^(b); (2) —(CH₂)_(n)—X—Pgroup; n is an integer from 0 to 6; m is an integer from 0 to 3; X isselected from (1) single bond; (2) oxygen atom; (3) —CO—NR^(c) group;(4) CO or SO₂ group; P is selected from (1) phenyl group, optionallysubstituted with one or more halogen atom, hydroxy, cyano, amino orC₁-C₄ alkyl group; (2) a saturated, partially unsaturated or aromatic4-7 membered ring containing 1-3 heteroatom selected from O, S, SO₂ andN; wherein said ring is optionally substituted with one or more halogenatom, oxo, hydroxy, cyano, amino or C₁-C₄ alkyl group; (3) C₅-C₈cycloalkyl group; R^(a) and R^(b) are (1) hydrogen atom, with theproviso that R^(a) and R^(b) can not be simultaneously hydrogen atom;(2) straight or branched C₁-C₆ alkyl group; (3) R^(a), R^(b) and thenitrogen atom to which they are both attached together form a saturated,partially unsaturated or aromatic 4-7 membered ring containing 0-3heteroatom (in addition to the nitrogen atom to which R^(a) and R^(b)attached) selected from O, S, SO₂ and N; wherein said ring is optionallysubstituted with one or more halogen atom, oxo, cyano, hydroxy or C₁-C₄alkyl group; R^(c) is hydrogen atom or C₁-C₄ alkyl group; R^(d) ishydrogen atom, C₁-C₄ alkyl group, C₁-C₄ hydroxyalkyl group, C₃-C₈cycloalkyl group; R^(e) is hydrogen atom, C₁-C₄ alkyl group, benzylgroup; A is (1) a C₄-C₇ cycloalkyl ring; (2) a saturated, partiallyunsaturated or aromatic 5-7 membered ring containing 0-4 heteroatomincluding W¹ selected from O, S, SO₂ and N; wherein said ring isoptionally substituted with one or more halogen atom, oxo, cyano,hydroxy, amino, phenyl or C₁-C₄ alkyl group; B is a saturated, partiallyunsaturated or aromatic 4-7 membered ring containing 1-3 heteroatomselected from O, S, SO₂ and N; wherein said ring is optionallysubstituted with one or more halogen atom, oxo, cyano, hydroxy, amino,phenyl or C₁-C₄ alkyl group; W¹ is carbon atom, nitrogen atom, or CHgroup; W² is oxygen atom, sulfur atom, NH, CH₂ or SO₂ group; or anoptical antipode or racemate or pharmaceutically acceptable saltthereof.
 13. A compound of claim 12 selected from the group consistingof4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(1-methyl-piperidin-3-ylmethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3-morpholin-4-yl-propyl)-[1,4]diazepan-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(3-piperidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-[1,4]diazepan-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-[4-(3-morpholin-4-yl-propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-[2-oxo-2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethyl]-benzamide;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide;N-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide;1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-piperidine-4-carboxylicacid amide;N-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride;N-(2-oxo-2-piperazin-1-yl-ethyl)-4-(2-phenoxy-phenylsulfamoyl)-benzamidehyrochlorid;N-[2-(4-amino-piperidin-1-yl)-2-oxo-ethyl]-4-(2-phenoxy-phenylsulfamoyl)-benzamidehydrochloride;4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride;N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzamidehydrochloride;4-(2-benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-(2-oxo-2-piperidin-1-yl-ethyl)-benzamide;N-(2-azepan-1-yl-2-oxo-ethyl)-4-(2-benzoyl-phenylsulfamoyl)-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-cyano-piperidin-1-yl)-2-oxo-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-oxo-2-(4-trifluoromethyl-piperidin-1-yl)-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(1-methyl-piperidin-3-ylmethyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-[4-(3-dimethylamino-propyl)-piperazin-1-yl]-2-oxo-ethyl}-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide;1-{2-[4-(2-benzoyl-phenylsulfamoyl)-benzoylamino]-acetyl}-piperidine-4-carboxylicacid amide;4-(2-benzoyl-phenylsulfamoyl)-N-(2-[1,4]diazepan-1-yl-2-oxo-ethyl)-benzamidehydrochloride;4-(2-benzoyl-phenylsulfamoyl)-N-(2-oxo-2-piperazin-1-yl-ethyl)-benzamidehydrochloride.
 14. A compound of claim 1 selected from the groupconsisting ofN-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-4-(2-phenoxy-phenylsulfamoyl)-benzamide;4-(2-benzoyl-phenylsulfamoyl)-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide;4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-{2-oxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperidin-1-yl]-ethyl}-benzamide;4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-N-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-benzamide.